U.S. patent application number 15/966758 was filed with the patent office on 2018-08-30 for method of making a multi-layer pad for use in determining an analyte concentration.
The applicant listed for this patent is Ascensia Diabetes Care Holdings AG. Invention is credited to Pamela J. Burson, Mihailo V. Rebec, Boru Zhu.
Application Number | 20180242913 15/966758 |
Document ID | / |
Family ID | 38564469 |
Filed Date | 2018-08-30 |
United States Patent
Application |
20180242913 |
Kind Code |
A1 |
Zhu; Boru ; et al. |
August 30, 2018 |
Method Of Making A Multi-Layer Pad For Use In Determining An
Analyte Concentration
Abstract
A multi-layer pad that is adapted to be used in determining an
analyte concentration is disclosed. The multi-layer pad includes a
first layer, a second layer, and a third layer. The first layer
includes an enzyme wherein the enzyme is adapted to assist in
determining the analyte concentration. The second layer is attached
to a first surface of the first layer. The second layer is made of
a skin-conforming material. The third layer is attached to a second
surface of the first layer wherein the first layer is located
between the second layer and the third layer. It is contemplated
that the multi-layer pad may also be a two layer system.
Inventors: |
Zhu; Boru; (Gibsonia,
PA) ; Rebec; Mihailo V.; (Bristol, IN) ;
Burson; Pamela J.; (Muncie, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ascensia Diabetes Care Holdings AG |
Basel |
|
CH |
|
|
Family ID: |
38564469 |
Appl. No.: |
15/966758 |
Filed: |
April 30, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12600403 |
Apr 15, 2010 |
9993202 |
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PCT/US06/62067 |
May 30, 2007 |
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15966758 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 5/1486 20130101;
G01N 33/525 20130101; C12Q 1/006 20130101; A61B 5/6833 20130101;
A61B 2562/0295 20130101; A61B 5/1451 20130101; C12Q 1/001 20130101;
A61B 5/14532 20130101; A61B 5/14546 20130101 |
International
Class: |
A61B 5/00 20060101
A61B005/00; G01N 33/52 20060101 G01N033/52; C12Q 1/00 20060101
C12Q001/00; A61B 5/145 20060101 A61B005/145; A61B 5/1486 20060101
A61B005/1486 |
Claims
1. A multi-layer pad adapted to be used in determining an analyte
concentration, the pad comprising: a first layer including an
enzyme, the enzyme being adapted to assist in determining the
analyte concentration; and a second layer being attached to the
first layer, the second layer being made of a skin-conforming
material.
2. The pad of claim 1, wherein the skin-conforming material
comprises a hydrogel.
3. The pad of claim 1, wherein the skin-conforming material is a
cross-linked hydrophillic polymer.
4. The pad of claim 1, wherein the second layer includes permeation
enhancers, humectants, surfactants, or combinations thereof.
5. The pad of claim 1, wherein the first layer further includes
fabric, porous membrane, or paper material.
6. The pad of claim 5, wherein the enzyme is physically absorbed on
or in the fabric, porous membrane, or paper material.
7. The pad of claim 5, wherein the enzyme is chemically immobilized
in the fabric, porous membrane, or paper material.
8. The pad of claim 1, wherein the enzyme is glucose oxidase.
9. The pad of claim 1, wherein the enzyme is glucose
dehydrogenase.
10. A multi-layer pad adapted to be used in determining an analyte
concentration, the pad comprising: a first layer including an
enzyme, the enzyme being adapted to assist in determining the
analyte concentration; a second layer being made of a
skin-conforming material; and a third layer in which the first
layer is located between the second layer and third layer.
11. The pad of claim 10, wherein the skin-conforming material
comprises a hydrogel.
12. The pad of claim 10, wherein the skin-conforming material is a
cross-linked hydrophillic polymer.
13. The pad of claim 10, wherein the second layer includes
permeation enhancers, humectants, surfactants or combinations
thereof.
14. The pad of claim 10, wherein the first layer further includes
fabric, porous membrane, or paper material.
15. The pad of claim 14, wherein the enzyme is physically absorbed
on or in the fabric, porous membrane, or paper material.
16. The pad of claim 14, wherein the enzyme is chemically
immobilized in the fabric, porous membrane, or paper material.
17. The pad of claim 10, wherein the enzyme is glucose oxidase.
18. The pad of claim 10, wherein the enzyme is glucose
dehydrogenase.
19. A method of continuously determining an analyte concentration,
the method comprising the acts of: is providing a multi-layer pad
comprising a first layer and a second layer, the second layer being
attached to the first layer, the first layer including an enzyme,
the enzyme being adapted to assist in determining the analyte
concentration, the second layer being made of a skin-conforming
material; providing a sensor that is adapted to assist in
determining the analyte concentration; placing the multi-layer pad
on the skin, the multi-layer pad being located between the sensor
and the skin; and determining the analyte concentration.
20. The method of claim 19, wherein the skin is the volar
forearm.
21. The method of claim 19, wherein the analyte is glucose.
22. The method of claim 19, wherein the sensor is an
electrochemical sensor.
23. The method of claim 19, wherein the skin-conforming material
comprises a hydrogel.
24. The method of claim 19, wherein the skin-conforming material is
a cross-linked hydrophillic polymer.
25. The method of claim 19, wherein the second layer includes
permeation enhancers, humectants, surfactants, or combinations
thereof.
26. The method of claim 19, wherein the first layer further
includes fabric, porous membrane, or paper material.
27. The method of claim 19, wherein the enzyme is glucose
oxidase.
28. The method of claim 19, wherein the enzyme is glucose
dehydrogenase.
29. A method of continuously determining an analyte concentration,
the method comprising the acts of: providing a multi-layer pad
comprising a first layer, a second layer, and a third layer, the
second layer being made of a skin-conforming material, the first
layer including an enzyme, the enzyme being adapted to assist in
determining the analyte concentration, the first layer being
located between the second layer and the third layer; providing a
sensor that is adapted to assist in determining the analyte
concentration; is placing the multi-layer pad on the skin, the
multi-layer pad being located between the sensor and the skin; and
determining the analyte concentration.
30. The method of claim 29, wherein the skin-conforming material
comprises a hydrogel.
31. The method of claim 29, wherein the skin-conforming material is
a cross-linked hydrophillic polymer.
32. The method of claim 29, wherein the second layer includes
permeation enhancers, humectants, surfactants, or combinations
thereof.
33. The method of claim 29, wherein the first layer further
includes fabric, porous membrane, or paper material.
34. The method of claim 29, wherein the enzyme is glucose
oxidase.
35. The method of claim 29, wherein the enzyme is glucose
dehydrogenase.
36. An electrochemical sensor system comprising: an electrochemical
sensor having a least a counter electrode and a working electrode;
a multi-layer pad coupled to the electrochemical sensor, the
multi-layer pad comprising a first layer and a second layer, the
second layer being attached to the first layer, the second layer
being biocompatible for skin contact, the first layer including an
enzyme, the enzyme being adapted to assist in determining the
analyte concentration.
37. The sensor system of claim 36, wherein the multi-layer pad is
attached to the electrochemical sensor.
38. The sensor system of claim 36, wherein the multi-layer pad is
attached to the electrochemical sensor via an adhesive.
39. The sensor system of claim 36, wherein the sensor further
includes a third electrode.
Description
FIELD OF THE INVENTION
[0001] The present invention relates generally to a multi-layer pad
and methods of using the same. One or more layers of the
multi-layer pad are hydrogels that are used to facilitate the
analysis of analytes that are found in the skin.
BACKGROUND OF THE INVENTION
[0002] The quantitative determination of analytes in body fluids is
of great importance in the diagnoses and maintenance of certain
physiological abnormalities. For example, lactate, cholesterol and
bilirubin should be monitored in certain individuals. In
particular, it is important that diabetic individuals frequently
check the glucose level in their body fluids to regulate the
glucose intake in their diets. The results of such tests can be
used to determine what, if any, insulin or other medication needs
to be administered.
[0003] One non-invasive method for obtaining a sample without using
a lancet is to take a transdermal sample of an analyte found in
interstitial fluid (ISF). In this method, a composition, such as a
hydrogel, is placed on the skin and assists in facilitating
diffusion of analytes from a user's skin to a sensing instrument or
meter, and in some cases (e.g., glucose) their subsequent products
after enzyme-catalyzed reactions. An enzyme in the hydrogel
composition assists in determining the analyte concentration of the
sample. This composition desirably possesses sufficient mechanical
and thermal stability to provide a relatively static, reactive and
aqueous contact between the dermal sampling site and sensing
instrument. One problem encountered with existing hydrogel
compositions is the tendency of the enzyme to leach therefrom. It
would be desirable to find a hydrogel composition that addresses
such a problem.
SUMMARY OF THE INVENTION
[0004] According to one embodiment, a multi-layer pad is adapted to
be used in determining an analyte concentration. The multi-layer
pad includes a first layer and a second layer. The first layer
includes an enzyme wherein the enzyme is adapted to assist in
determining the analyte concentration. The second layer is attached
to the first layer and is made of a skin-conforming material.
[0005] According to another embodiment, a multi-layer pad is
adapted to be used in determining an analyte concentration. The
multi-layer pad includes a first layer, a second layer, and a third
layer. The first layer includes an enzyme that is adapted to assist
in determining the analyte concentration. The second layer is
attached to a first surface of the first layer and is made of a
skin-conforming material. The third layer is attached to a second
surface of the first layer and the first layer is located between
the second layer and the third layer.
[0006] Additionally, a method of continuously determining an
analyte concentration is disclosed. A multi-layer pad is provided
and comprises a first layer and a second layer, wherein the second
layer is attached to the first layer. The first layer includes an
enzyme that is adapted to assist in determining the analyte
concentration. The second layer is made of a skin-conforming
material. A sensor that is adapted to assist in determining the
analyte concentration is also provided. The multi-layer pad is
placed on the skin and is located between the sensor and the skin.
The method further includes the act of determining the analyte
concentration.
[0007] In another embodiment, a method of continuously determining
an analyte concentration is disclosed. A multi-layer pad is
provided and includes a first layer, a second layer, and a third
layer. The second layer is made of a skin-conforming material. The
first layer includes an enzyme that is adapted to assist in
determining the analyte concentration. The first layer is located
between the second layer and the third layer. A sensor that is
adapted to assist in determining the analyte concentration is also
provided. The multi-layer pad is placed on the skin and is located
between the sensor and the skin. The method further comprises the
act of determining the analyte concentration.
[0008] The above summary of the present invention is not intended
to represent each embodiment, or every aspect, of the present
invention. Additional features and benefits of the present
invention are apparent from the detailed description and figures
set forth below.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1a is a two-layer pad according to one embodiment.
[0010] FIG. 1b is the two-layer pad of FIG. 1 applied to skin.
[0011] FIG. 2 is a three-layer pad according to one embodiment.
[0012] FIG. 3 is a five-layer pad according to one embodiment.
[0013] FIG. 4 is an electrochemical sensor according to one
embodiment.
[0014] FIG. 5 is an electrochemical sensor system including the
electrochemical sensor of FIG. 4 and the pad of FIG. 2.
DESCRIPTION OF ILLUSTRATED EMBODIMENTS
[0015] The present invention is directed to a novel multi-layer pad
that is adapted to assist in determining an analyte concentration.
The multi-layer pad exhibits desirable properties necessary for a
transdermal method of determining analytes in one method. In one
embodiment, the multi-layer pad is adapted to be used to assist in
determining an analyte concentration of interstitial fluid (ISF)
with a sensor. More specifically, the multi-layer pad is adapted to
serve as an interface generally between and coupling the skin and
the sensor.
[0016] Analytes that may be measured with a multi-layer pad include
glucose, lipid profiles (e.g., cholesterol, triglycerides, LDL and
HDL), microalbumin, fructose, lactate, or bilirubin. It is
contemplated that other analyte concentrations may be determined.
The analytes may be in, for example, a whole blood sample, a blood
serum sample, a blood plasma sample, other body fluids like ISF
(interstitial fluid) and urine, and non-body fluids. As used within
this application, the term "concentration" refers to an analyte
concentration, activity (e.g., enzymes and electrolytes), titers
(e.g., antibodies), or any other measure concentration used to
measure the desired analyte.
[0017] Referring initially to FIG. 1a, a multi-layer pad 10 is
shown according to one embodiment. The pad 10 of FIG. 1a comprises
a first layer 12 and a second layer 14. The first layer 12 is
adjacent to the second layer 14.
[0018] The first layer 12 is generally a fabric, a porous membrane,
or a paper material. The first layer 12 contains enzymes that may
be added to the fabric, porous membrane, or paper material by
several methods. For example, the enzymes may be physically
absorbed and dried on or in the fabric, porous membrane, or paper
material. Alternatively, the enzymes may be chemically immobilized
to or within the fabric, porous membrane, or paper material.
[0019] The fabric may be made of several materials including, but
not limited to, naturally occurring materials such as silk and
cellulose, and synthetic polymeric materials such as polyethylene
terephtalate, polyurethane, and glass fibers. To improve surface
biocompatibility toward enzymes, the fabric materials may be
pretreated with glow plasma, ion implantation, ozone, ultraviolet
(UV), vacuum ultraviolet (VUV), chemical etching or surface
modification, or pre-coated or grafted with hydrophilic polymers
and/or proteins. It is contemplated that other materials may be
used to form the fabric. One specific example of a polymer that may
be used to form the fabric is polyethylene terephtalate fabric.
However, it is contemplated that other polymeric materials may also
be used to form the fabric.
[0020] The porous membrane may be made of several materials
including, but not limited to, cellulose and its derivatives,
nylon, polyacrylonitrile, polycarbonate, polypropylene,
polysulfone, or polyvinyl chloride. To improve surface
biocompatibility toward enzymes, the hydrophilic membranes may be
pretreated with glow plasma, ion implantation, ozone, ultraviolet
(UV), vacuum ultraviolet (VUV), chemical etching or surface
modification, or pre-coated or grafted with hydrophilic polymers
and/or proteins.
[0021] The paper material may be made of several materials
including, but not limited to, cellulose and its derivatives. It is
contemplated that other materials may be used to form the paper
material. One specific example of such a paper material is
Kimwiper.RTM. EX-L paper wiper from Kimberly-Clark. However, it is
contemplated that other paper materials such as filter paper may be
used.
[0022] The enzymes to be added to the fabric or paper material
assist in determining the concentration of an analyte. Depending on
the analyte, an enzyme may assist in converting the analyte into a
species amenable to detection, such as electrochemical detection.
One example of an enzyme that may be used in determining glucose is
glucose oxidase. It is contemplated that other enzymes may be used
to assist in determining glucose, such as glucose dehydrogenase. If
other analytes are of interest, an appropriately selected enzyme
may assist in determining the concentration of that analyte.
[0023] As discussed above, the enzyme can be physically adsorbed or
chemically immobilized onto the fabric, membrane, or paper material
that is to form the first layer 12. For physical adsorption, the
enzyme may be dissolved into a buffer solution, for instance,
phosphate-buffered saline solution. The first layer 12 may be
formed by immersing the fabric, membrane or paper material in the
enzyme-containing solution and subsequently dried. Water-soluble
polymers may also be added into the enzyme solution prior to
substrate immersion. Once the fabric, membrane or paper material is
immersed into the enzyme solution, the water-soluble polymer may be
adsorbed onto the substrate alone with the enzyme. Upon drying, the
presence of the water-soluble polymer may enhance the physical
entrapment of the enzyme.
[0024] For chemical immobilization, the enzyme may be fixed with a
cross-linking agent such as glutaraldehyde. To improve enzyme
activity, the enzyme may be pre-mixed with another protein such as
albumin or gelatin. In another embodiment, a certain pre-treatment
may be performed to introduce some functional groups, including
amino or carboxyl, onto the surface of the substrate. The
immobilization may also be done by forming chemical bonds between
enzyme molecules and the substrate.
[0025] Besides enzymes, it is also contemplated that other
materials may be included in the first layer 12 such as
surfactants, polysaccharides, and salts, to enhance enzyme
long-term stability.
[0026] The second layer 14 is made of a skin-conforming material. A
"skin-conforming material" as defined herein includes materials
that conform to the skin and maintain desirable contact with the
skin. One non-limiting example of a skin-conforming material is a
hydrogel. Other potential materials include porous polymers and
spongy commercial materials, such as membranes that have a lot of
open space that are soaked in a buffered liquid. Accordingly, in
one embodiment, the second layer 14 is a hydrogel. The hydrogel
should be able to maintain a water content from about 40% to about
98%, more desirably from about 80% to about 95%, to facilitate fast
diffusion of analytes. The second layer 14 is a desirably optimized
to have good biocompatibility for skin contact.
[0027] The second layer 14, in another embodiment, is a
cross-linked hydrophilic polymer. In another embodiment, the second
layer 14 may be a polymer with a certain hydrophilic and
hydrophobic balance. To form a cross-linked polymer in one
embodiment, the second layer 14 is polymerized from a monomer
mixture or coated from a polymer solution. One specific
non-limiting example of a monomer solution to form a cross-linked
polymer includes N-vinyl pyrrolidone, vinyl acetate, diethylene
glycol divinyl ether, and
(2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiopheone, which is an
UV initiator, at a pre-determined ratio. It is contemplated that
other cross-linked hydrophillic polymers may be formed using
polyethylene glycol acrylates, acrylic acid, and acrylamide.
[0028] In the above described embodiment, an UV initiator may be
used and therefore free-radical polymerization of the first layer
12 with the second layer 14 is initiated by UV irradiation. Other
methods to initiate co-polymerization may also be used including
thermal initiation (with thermal initiator), .gamma.-ray, and
electron beam (with or without initiator).
[0029] In another embodiment, the second layer 14 is formed from a
coated polymer solution. One non-limiting example of a coated
polymer solution includes the use of sodium alginate and
poly(ethylene oxide). Alginate is a natural copolymer of two uronic
acides, D-mannuronic acid and L-guluronic acid. One method to
cross-link the polymer coating described above with the first layer
12 so as to form the second layer 14, is to associate the polymer
solution with calcium ions. While not being bound by theory,
calcium ions are believed to bind to the polymer when there are two
neighboring guluronic acid residues. This binding forms an
insoluble network.
[0030] It is contemplated that other materials may be used to form
the second layer 14 such as .omega.-methoxy-.alpha.-(chloromethyl
benzoyl) polyethylene glycol, a hydrophilic polymer with
photo-sensitive functional groups. The cross-linking reaction may
be initiated with UV irradiation to form the second layer 14 after
a polymer solution is applied onto the first layer 12. In another
embodiment, hydrophilic polymers in solution may be coated and
dried on the first layer 12. The cross-linking reaction may be
initiated with plasma exposure under inert gas such as, for
example, argon or nitrogen. The cross-linking reaction may also be
initiated with .gamma.-ray, or an electron beam.
[0031] To provide and maintain openings formed in the skin, the
second layer 14 may include a permeation enhancer. Non-limiting
examples of permeation enhancers that may be used include squalene,
unsaturated fatty acids, glycerol derivatives of fatty alcohols,
dimethylsulfoxide, and alkyl esters of fatty acids. Furthermore,
where desirable to keep the skin moist, the second layer 14 may
also include humectants. Non-limiting examples of humectants that
may be used in the second layer 14 include glycerol, hexylene
glycol and sorbitol, maltitol, polydextrose, propylene glycol,
lactic acid, and lactate metal salts. To assist the multi-layer pad
10 in obtaining desirable contact with the skin, the second layer
14 may also include surfactants. Non-limiting examples of
surfactants that may be used include alkyl phenols such as
TRITON.RTM. X-100 (octyl phenol ethoxylate having a molecular
formula of C.sub.14H.sub.22O(C.sub.2H.sub.4O).sub.n where an
average "n" is 9 or 10), and sorbitol and sorbitol derivatives such
as the TWEEN.TM. series.
[0032] It is also contemplated that other materials may be included
in the second layer 14. For example, an electrolyte may be included
in the second layer 14. The electrolyte may perform multiple
functions. First, the electrolyte is a chemical compound that
ionizes when dissolved to produce an electrically-conductive
medium. Second, the electrolyte desirably contains a high salt
concentration so that when used in applications contacting the
skin, it assists in exerting osmotic pressure on the skin. Thus,
electrolytes are desired in skin-contacting layers such as the
second layer 14. By exerting osmotic pressure on the skin, the
electrolyte assists in driving out the interstitial fluid (ISF)
that contains the analyte. Non-limiting examples of electrolytes
that may be used include sodium and potassium salts of chloride,
phosphate, citrate, acetate and lactate.
[0033] As discussed above, the multi-layer pad 10 of FIG. 1a may be
applied to the skin. An example of the multi-layer pad 10
contacting skin 15 is shown in FIG. 1b.
[0034] Referring now to FIG. 2, a multi-layer pad 20 is disclosed
in another embodiment. The multi-layer pad 20 of FIG. 2 comprises a
first layer 12, a second layer 22, and a third layer 24. The second
layer 22 is adjacent to a first surface of the first layer 12 and
the third layer 24 is adjacent to a second surface of the first
layer 12. Thus, the first layer 12 with the enzyme is located
between the second layer 22 and the third layer 24. By locating the
enzymes in between the second layer 22 and the third layer 24, the
ability to prevent or inhibit the enzymes from leaching is
enhanced. Additionally, the skin interaction with the enzymes is
also reduced or eliminated. If UV is used to initiate cross-linking
reaction as described above in reference to FIG. 1a, the location
of the enzymes in the first layer 12 may prevent or inhibit
dramatic loss in activity thereto. Furthermore, by providing the
first layer 12 between two opposing layers 22, 24, different
materials may be selected to form the second layer 22 and the third
layer 24. For instance, the second layer 22 may be optimized for
skin contact while the third layer 24 may be optimized for the
redox-reaction. The second layer 22 and the third layer 24 may be
made of the materials that were described in reference to the
second layer 14. The multi-layer pad 20 may also be applied to the
skin in a similar manner as multi-layer pad 10 in FIG. 1b.
[0035] FIG. 3 illustrates a multi-layer pad 30 according to another
embodiment. The multi-layer pad 30 includes the first layer 12, a
second layer 32, a third layer 34, a fourth layer 36, and a fifth
layer 38. The second layer 32 is adjacent to the first surface of
the first layer 12 while the third layer 34 is adjacent to the
second surface of the first layer 12. The fourth layer 36 is
adjacent to the second layer 32 on the surface opposite the first
layer 12. And the fifth layer 38 is adjacent to the third layer 34
on the surface opposite the first layer 12. The outer layers (the
second layer 32, the third layer 34, the fourth layer 36 and the
fifth layer 38) may be optimized for different purposes in much the
same ways as the outer layers of the multi-layer pad 20 (the second
layer 22 and the third layer 24) of FIG. 2 may be optimized for
different purposes. The layers 34 and 38, 32 and 36, may be made
from different or same materials. For example, the third layer 34
and the fifth layer 38 may be hydrogel layers. These layers 34, 38
may be developed from the same hydrophilic polymers while
presenting different porosity to improve diffusion selectivity. In
another example, one or both of the fourth layer 36 or fifth layer
38 may be another porous membrane, paper, and/or fabric material to
improve the mechanical properties of the multi-layer pad 30.
[0036] As previously mentioned, the multi-layer pads 10, 20, or 30
are adapted to serve as an interface generally between and coupling
the skin and the sensor according to one method. In one method, the
sensor determines the concentration of the desired analyte from a
sampling of the ISF. In one embodiment, the sensor is an
electrochemical sensor.
[0037] Referring to FIG. 4, an electrochemical sensor 40 is shown
according to one embodiment. The electrochemical sensor 40 includes
at least a counter electrode 42 and a working electrode 44. Other
electrodes such as a detection electrode 46 may be included in the
electrochemical sensor 40. It is contemplated that more or less
electrodes can be formed in the method of the present invention.
For example, the test sensor may include exactly two electrodes or
at least three electrodes. The exactly two electrodes may be a
working electrode and a counter electrode in which an
electrochemically created current flow when these electrodes are
electrically connected and a potential is created between them.
[0038] As shown in FIG. 5, the electrochemical sensor system 50
includes the electrochemical sensor 40 of FIG. 4, the multi-layer
pad 20 and an adhesive ring 54. In this embodiment, the adhesive
ring 54 has two functions: (a) to cover a portion of the
multi-layer pad 20 and secure it to the electrochemical sensor 40;
and (b) to secure the electrochemical sensor system 50, including
the multi-layer pad 20, to the skin.
[0039] In one method of determining an analyte concentration, a
multi-layer pad (e.g., multi-layer pad 10, 20, or 30) is added to
the skin. The multi-layer pad may be located at a skin site such as
the volar forearm between the wrist and elbow. It is contemplated
that the multi-layer pad may be located at other skin sites such as
the abdomen. The skin may then be pre-treated in this method to
increase the skin permeability. One example of pre-treating is to
use ultrasound energy to disrupt the lipid bilayer of the stratum
corneum so as to increase the skin permeability. By increasing the
skin permeability, the amount of diffused analyte from the dermis
ISF is increased. This results in improved sampling of the analytes
of interest (e.g., glucose) found in the ISF. A sensor determines
the concentration of the desired analyte after contacting the
multi-layer pad and the skin.
[0040] One non-limiting source of an ultrasound energy system is
Sontra SonoPrep.RTM. ultrasonic skin permeation system marketed by
Sontra Medical Corporation. The SonoPrep.RTM. system applies
relatively low frequency ultrasonic energy to the skin for a
limited duration (from about 10 to 20 seconds). The ultrasonic horn
contained in the device vibrates at about 55,000 times per second
(55 KHz) and applies energy to the skin through the liquid-coupling
medium to create cavitation bubbles that expand and contract in the
coupling medium. That cavitation results in the creation of
cavities in the stratum cornium.
EXAMPLES
Example 1
[0041] 5 g of glucose oxidase (GO) was dissolved in a
phosphate-buffered saline solution containing 0.4 M of lactic acid
at pH 7.2. Kimwiper.RTM. EX-L paper wiper from Kimberly-Clark was
immersed in the 5 wt % GO solution for about 30 minutes at room
temperature. The paper wiper was then removed from the GO solution
and dried in a low humidity room at room temperature. The
GO-containing paper wiper was then immersed in a monomer solution.
The monomer solution contained 60 parts of N-vinyl pyrrolidone, 40
parts of vinyl acetate, 1 part of diethylene glycol divinyl ether,
and 1 part of (2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiopheone,
which is an UV initiator. The co-polymerization was then initiated
under UV irradiation. Upon completing the polymerization with no
monomer left over, a three layer structure was formed. After
hydrating the polymeric outer layers, the multi-layer pad is
adapted to be directly used.
Example 2
[0042] 5 g of glucose oxidase (GO) and 2 g of calcium chloride
(CaCl.sub.2) were dissolved in 93 g of nanopure water.
Kimwiper.RTM. EX-L paper wiper from Kimberly-Clark was immersed in
the GO-CaCl.sub.2 solution for 30 minutes at room temperature. The
paper wiper was then removed from the GO-CaCl.sub.2 solution and
dried in a low humidity room at room temperature. A solution
containing 4 wt % of sodium alginate and 1 wt % of poly(ethylene
oxide) was coated onto both sides of the GO-CaCl.sub.2 treated
paper wiper and then wrapped with a plastic wrap film. The coated
film was then exposed to a temperature that ranged from about 2 to
about 8.degree. C. for a duration of up to 6 months. It is believed
that calcium ions from the paper wiper eventually dissolved and
diffused into the polymer solutions coated on both sides and
crosslinked the sodium alginate. Alginate is a natural copolymer of
two uronic acids, D-mannuronic acid and L-guluronic acid. While not
being bound by theory, it is believed that calcium ions bind to the
polymer whenever there are two neighboring guluronic acid residues
and form an insoluble network.
Example 3
[0043] 5 g of glucose oxidase (GO) and 95 g of phosphate-buffered
saline solution. Kimwiper.RTM. EX-L paper wiper from Kimberly-Clark
was immersed in the GO solution for about 30 minutes at room
temperature. The paper wiper was then removed from the GO solution
and dried in a low humidity room at room temperature. A solution
containing 4 wt % of sodium alginate and 1 wt % of poly(ethylene
oxide) was coated onto both sides of the GO-treated paper wiper. A
5 wt % of calcium chloride solution was then sprayed over each
surface and the coated wiper was wrapped with plastic wrap film.
The coated film was then exposed to a temperature that ranged from
about 2 to about 8.degree. C. for a duration of up to 6 months.
While not being bound by theory, it is believed that calcium ions
from the paper wiper eventually dissolved and diffused into the
polymer solutions coated on both sides and crosslinked the sodium
alginate so as to form an insoluble network.
Example 4
[0044] 5 g of glucose oxidase (GO) was dissolved in 95 g of
phosphate-buffered saline solution. Kimwiper.RTM. EX-L paper wiper
from Kimberly-Clark was immersed in the GO solution for 30 minutes
at room temperature. The paper wiper was then removed from the GO
solution and dried in a low humidity room at room temperature. A
solution containing 4 wt % of sodium alginate and 1 wt % of
poly(ethylene oxide) was mixed with CaCO.sub.3 powder. This mixture
was then coated onto both sides of GO-treated paper wiper. An
acetic acid solution was then sprayed over each surface and the
coated wiper was wrapped with plastic wrap film. The coated film
was then exposed to a temperature that ranged from about 2 to about
8.degree. C. for a duration up to 6 months. While not being bound
by theory, it is believed that calcium ions from the paper wiper
eventually dissolved and diffused into the polymer solutions coated
on both sides and crosslinked the sodium alginate so as to form an
insoluble network.
Example 5
[0045] 5 g of glucose oxidase (GO) was dissolved in 95 g of
phosphate-buffered saline solution. Kimwiper.RTM. EX-L paper wiper
from Kimberly-Clark was immersed in the GO solution for 30 minutes
at room temperature. The paper wiper was then removed from the GO
solution and dried in a low humidity room at room temperature. A 3
wt % of gelatin solution in nanopure water was coated onto both
sides of the GO-treated paper wiper. Each surface of the paper
wiper was then exposed under UV for 30 minutes at room temperature.
Gelatin molecules were cross-linked with each other under UV
irradiation so as to form an insoluble network.
[0046] Alternative Embodiment A
[0047] A multi-layer pad adapted to be used in determining an
analyte concentration, the pad comprising: [0048] a first layer
including an enzyme, the enzyme being adapted to assist in
determining the analyte concentration; and [0049] a second layer
being attached to the first layer, the second layer being made of a
skin-conforming material.
[0050] Alternative Embodiment B
[0051] The pad of Alternative Embodiment A wherein the
skin-conforming material comprises a hydrogel.
[0052] Alternative Embodiment C
[0053] The pad of Alternative Embodiment A wherein the
skin-conforming material is a cross-linked hydrophillic
polymer.
[0054] Alternative Embodiment D
[0055] The pad of Alternative Embodiment A wherein the second layer
includes permeation enhancers, humectants, surfactants, or
combinations thereof.
[0056] Alternative Embodiment E
[0057] The pad of Alternative Embodiment A wherein the first layer
further includes fabric, porous membrane, or paper material.
[0058] Alternative Embodiment F
[0059] The pad of Alternative Embodiment E wherein the enzyme is
physically absorbed on or in the fabric, porous membrane, or paper
material.
[0060] Alternative Embodiment G
[0061] The pad of Alternative Embodiment E wherein the enzyme is
chemically immobilized in the fabric, porous membrane, or paper
material.
[0062] Alternative Embodiment H
[0063] The pad of Alternative Embodiment A wherein the enzyme is
glucose oxidase.
[0064] Alternative Embodiment I
[0065] The pad of Alternative Embodiment A wherein the enzyme is
glucose dehydrogenase.
[0066] Alternative Embodiment J
[0067] A multi-layer pad adapted to be used in determining an
analyte concentration, the pad comprising: [0068] a first layer
including an enzyme, the enzyme being adapted to assist in
determining the analyte concentration; [0069] a second layer being
made of a skin-conforming material; and [0070] a third layer in
which the first layer is located between the second layer and third
layer.
[0071] Alternative Embodiment K
[0072] The pad of Alternative Embodiment J wherein the
skin-conforming material comprises a hydrogel.
[0073] Alternative Embodiment L
[0074] The pad of Alternative Embodiment J wherein the
skin-conforming material is a cross-linked hydrophillic
polymer.
[0075] Alternative Embodiment M
[0076] The pad of Alternative Embodiment J wherein the second layer
includes permeation enhancers, humectants, surfactants or
combinations thereof.
[0077] Alternative Embodiment N
[0078] The pad of Alternative Embodiment J wherein the first layer
further includes fabric, porous membrane, or paper material.
[0079] Alternative Embodiment O
[0080] The pad of Alternative Embodiment N wherein the enzyme is
physically absorbed on or in the fabric, porous membrane, or paper
material.
[0081] Alternative Embodiment P
[0082] The pad of Alternative Embodiment N wherein the enzyme is
chemically immobilized in the fabric, porous membrane, or paper
material.
[0083] Alternative Embodiment Q
[0084] The pad of Alternative Embodiment J wherein the enzyme is
glucose oxidase.
[0085] Alternative Embodiment R
[0086] The pad of Alternative Embodiment J wherein the enzyme is
glucose dehydrogenase.
[0087] Alternative Process S
[0088] A method of continuously determining an analyte
concentration, the method comprising the acts of: [0089] providing
a multi-layer pad comprising a first layer and a second layer, the
second layer being attached to the first layer, the first layer
including an enzyme, the enzyme being adapted to assist in
determining the analyte concentration, the second layer being made
of a skin-conforming material; [0090] providing a sensor that is
adapted to assist in determining the analyte concentration; [0091]
placing the multi-layer pad on the skin, the multi-layer pad being
located between the sensor and the skin; and [0092] determining the
analyte concentration.
[0093] Alternative Process T
[0094] The method of Alternative Process S wherein the skin is the
volar forearm.
[0095] Alternate Process U
[0096] The method of Alternative Process S wherein the analyte is
glucose.
[0097] Alternate Process V
[0098] The method of Alternative Process S wherein the sensor is an
electrochemical sensor.
[0099] Alternative Process W
[0100] The method of Alternative Process S wherein the
skin-conforming material comprises a hydrogel.
[0101] Alternative Process X
[0102] The method of Alternative Process S wherein the
skin-conforming material is a cross-linked hydrophillic
polymer.
[0103] Alternative Process Y
[0104] The method of Alternative Process S wherein the second layer
includes permeation enhancers, humectants, surfactants, or
combinations thereof.
[0105] Alternative Process Z
[0106] The method of Alternative Process S wherein the first layer
further includes fabric, porous membrane, or paper material.
[0107] Alternative Process AA
[0108] The method of Alternative Process S wherein the enzyme is
glucose oxidase.
[0109] Alternative Process AB
[0110] The method of Alternative Process S wherein the enzyme is
glucose dehydrogenase.
[0111] Alternative Process AC
[0112] A method of continuously determining an analyte
concentration, the method comprising the acts of: [0113] providing
a multi-layer pad comprising a first layer, a second layer, and a
third layer, the second layer being made of a skin-conforming
material, the first layer including an enzyme, the enzyme being
adapted to assist in determining the analyte concentration, the
first layer being located between the second layer and the third
layer; [0114] providing a sensor that is adapted to assist in
determining the analyte concentration; [0115] placing the
multi-layer pad on the skin, the multi-layer pad being located
between the sensor and the skin; and [0116] determining the analyte
concentration.
[0117] Alternative Process AD
[0118] The method of Alternative Process AC wherein the
skin-conforming material comprises a hydrogel.
[0119] Alternative Process AE
[0120] The method of Alternative Process AC wherein the
skin-conforming material is a cross-linked hydrophillic
polymer.
[0121] Alternative Process AF
[0122] The method of Alternative Process AC wherein the second
layer includes permeation enhancers, humectants, surfactants, or
combinations thereof.
[0123] Alternative Process AG
[0124] The method of Alternative Process AC wherein the first layer
further includes fabric, porous membrane, or paper material.
[0125] Alternative Process AH
[0126] The method of Alternative Process AC wherein the enzyme is
glucose oxidase.
[0127] Alternative Process AI
[0128] The method of Alternative Process AC wherein the enzyme is
glucose dehydrogenase.
[0129] Alternative Embodiment AJ
[0130] An electrochemical sensor system comprising: [0131] an
electrochemical sensor having a least a counter electrode and a
working electrode; [0132] a multi-layer pad coupled to the
electrochemical sensor, the multi-layer pad comprising a first
layer and a second layer, the second layer being attached to the
first layer, the second layer being biocompatible for skin contact,
the first layer including an enzyme, the enzyme being adapted to
assist in determining the analyte concentration.
[0133] Alternative Embodiment AK
[0134] The sensor system of Alternative Embodiment AJ wherein the
multi-layer pad is attached to the electrochemical sensor.
[0135] Alternative Embodiment AL
[0136] The sensor system of Alternative Embodiment AJ wherein the
multi-layer pad is attached to the electrochemical sensor via an
adhesive.
[0137] Alternative Embodiment AM
[0138] The sensor system of Alternative Embodiment AJ wherein the
sensor further includes a third electrode.
[0139] While the invention is susceptible to various modifications
and alternative forms, specific embodiments and methods thereof
have been shown by way of example in the drawings and are described
in detail herein. It should be understood, however, that it is not
intended to limit the invention to the particular forms or methods
disclosed, but, to the contrary, the intention is to cover all
modifications, equivalents and alternatives falling within the
spirit and scope of the invention as defined by the appended
claims.
* * * * *